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Seaweed metabolism

A transversal field of application is marine biology, as it is a transversal field with respect to issues in integrative biology, dynamical systems and sequence analysis. In this context, we have a long-term collaboration with the Station Biologique de Roscoff (CNRS/UPMC), supported by the Investment for the Future (PIA) plan Idealg.

ln the framework of integrative biology and sequence analysis, our methods based on combinatorial optimization for the reconstruction of genome-scale metabolic networks and on classification of enzyme families based on local and partial alignments allowed the seaweed metabolism E. Siliculosus to be deciphered . The study of the HAD family of proteins with Protomata-learner allowed sub-families to be deciphered and classified, and the metabolic map reconstructed with Meneco enabled the reannotation of 56 genes within the E. siliculosus genome. These approaches also shed light on evolution of metabolic processes. For example, E. siliculosus we proved that has the potential to produce phenylalanine and tyrosine from prephenate and arogenate, but does not possess a phenylalanine hydroxylase as found in other stramenopiles. It also possesses the complete eukaryote molybdenum cofactor biosynthesis pathway, as well as a second molybdopterin synthase that was most likely acquired via horizontal gene transfer from cyanobacteria by a common ancestor of stramenopiles. As a further study, we reconstructed the metabolic network of a symbiot bacterium Ca. P. ectocarpi and used this reconstructed network to decipher interactions within the algal-bacteria holobiont, revealing several candidates metabolic pathways for algal-bacterial interactions. Our analyses indicate that histidinol or histidine may be provided by symbiotic bacteria such as Ca. P. ectocarpi, which encodes all enzymes of the histidine biosynthetic pathway.

Similarily, our analyses suggest that the bacterium Ca. P. ectocarpi is able to provide both beta-alanine and vitamin B5 to the seaweed via the phosphopantothenate biosynthesis pathway. An experimental Ph.D. thesis is currently ongoing at the Station Biologique de Roscoff to isolate the seaweed strain. Experimentations to validate these hypotheses will be performed during winter 2017.

Ph-D thesis defended in 2016

One thesis and one habilitation thesis were defended within the Dyliss team in 2016.

Olivier Dameron surveyed his contributions to the topic of Ontology-based methods for analyzing life science data [habilitation thesis][1]

Aymeric Antoine-Lorquin evidenced the need of expressive grammars to capture the complexity of biological patterns in DNA and RNA sequences [[2]thesis[3]][2]

Elucidating the functioning of extremophile consortiums of bacteria

On of our main issues is the understanding of bacteria living in extreme environments, mainly in collaboration with the group of bioinformatics at Universidad de Chile (co-funded by the Center of Mathematical Modeling, the Center of Regulation Genomics and Inria-Chile, Ciric-omics project).

In order to elucidate the main characteristics of these bacteria, our integrative methods were developed to identify the main groups of regulators for their specific response in their living environment. The integrative biology tools Meneco, Lombarde and Shogen have been designed in this context. In particular, genome-scale metabolic network been recently reconstructed and studied with the Meneco and Shogen approaches, especially on bacteria involved in biomining processes. From the public genomes of five bacterial strains involved in copper bioleaching: Acidiphilium cryptum, Acidithiobacillus ferrooxidans, Acidithiobacillus thiooxidans, Leptospirillum ferriphilum and Sulfobacillus thermosulfidooxidans. All are capable of surviving in extreme environment such as mines. They are typical example of a non-modeled species with interesting economical features. Nonetheless, elucidating their capability to survive in mines or to decompose copper ore is far from trivial, mainly because this bacteria still cannot be genetically perturbed.

Our analyses based on our tools suggested that only few functional metabolic genes are horizontally transferred within the consortium of bacteria and that no single bacterial strain can accomplish by itself the whole copper bioleaching. Our analysis pinpointed a functional compartmentalization among the investigated species and exhibits putative bacterial interactions necessary for promoting these pathways. Interestingly, beyond the simple mapping of bacterial strain metabolism on these pathways of interest, we depicted the functional units, or operons, that must be combined to genetically monitor the bacterial participation as a whole in the bioleaching process, as well as specific transporters that must be further investigated to understand putative metabolic collaborative processes at the community level. Further experimentations require to acquire bioreactors and to cultivate the considered strains. This is planed by our collaborators in Chile.

Ph-D thesis defended in 2015

Clovis Galiez studied structural fragments and their application to the identification of viral structurak proteins [thesis[3]]

Vincent Picard designed a probabilistic framework inspired by the flux balance analysis formalism to refutate reaction networks based on data covariance [thesis[5]]

Pea aphid phenotypic plasticity

Among our applicative projets, we collaborated with the IGEPP (Inra) laboratory in Rennes to decipher regulators of reproduction for the pea aphid, an insect that is a pest on plants. In terms of biological output of the network studies on the pea aphid microRNAs, we have identified one new microRNA - apmir-3019 - who has more than 900 putative mRNA targets. All these targets are differentially expressed between sexual and asexual embryos. At that stage, there are two hypotheses: either this microRNA plays a role of a sponge regulating the basal steady-state level of most of the mRNAs, or this microRNA has a key role in the process of interest (sexual versus asexual embryogenesis). We recently demonstrated that this microRNA also targets many long non-coding RNA of the pea aphid. The next steps are i) to include lncRNA in the network using formal concepts on three elements (mRNAs, microRNAs, lncRNAs) and ii) to test by biological means in aphid (genetic knockdown) the putative role of apmir-3019 in sexual or asexual embryogenesis.

Ph-D thesis defended in 2014

Four theses were defended within the Dyliss team in 2014, on several subjects and applications.

Sylvain Prigent studied metabolic network completion (gap-filling) with a combinatorial approach implemented in a logical paradigm and applied it to the study of brown algae [thesis][7]

Gaëlle Garet combined multiple and partial local alignments and formal concept analysis to decipher the function of enzymatic families. [thesis][8]

Santiago Videla designed a loop for the inference, control and discrimination of boolean networks from phosphoproteomics data [thesis][9]

TGF-beta signalling network

TGF-beta is a multifunctional cytokine that regulates mammalian development, differentiation, and homeostasis. As a growth inhibitor of epithelial, endothelial, and hematopoietic cells, TGF-beta is a potent anticancer agent in normal tissue. At the opposite TGF-beta acts as a promoter of tumor by inducing the hallmarks of the cancer. Consequently targeting the deleterious effects of TGF-beta without affecting its physiological role is the common goal of therapeutic strategies. While several strategies based on blocking TGF-beta antibodies or small inhibitors of TGF-beta receptors have been investigated, they did not take into account the impact of the (extracellular matrix) ECM remodeling that regulates TGF-beta bioavailability and the complexity of TGF-beta-dependent signaling pathways which regulate both physiological and pathological processes depending on context. In accordance with this, our collaborators in the IRSET lab. in Rennes recently demonstrated the benefical anti-tumor effect of the interplay between TGF-beta signaling and the CD103 integrin pathway. At the opposite we have previously demonstrated that the disintegrin ADAMTS1 promotes TGF-beta activation in chronic liver disease and using in silico approach, we recently characterized interaction with inhibitor peptide to block such effects . Additionally, the quantitative balance between components is sufficient to modulate TGF-beta effects. In that context we demonstrated that the ratio of TGFBR2 to TGFBR1 receptors concentrations can be used to discriminate between metastable regimes of TGF-beta signaling model and predict the tumor cell aggressiveness. Consequently, deciphering protumor versus antitumor signaling requires to take into account a system-wide view and develop predictive models for therapeutic benefit.

For that purpose we developed Cadbiom that permits to investigate TGF-beta signaling and all crosstalks with other pathways. Using Cadbiom, we have integrated 137 signaling pathways into a single cell signaling model containing more than 9,000 molecular components. We explored 15,934 trajectories regulating 145 target genes of TGF-beta and identified gene networks associated with innate immune response to viral infection that combine TGF-beta and interleukine signaling pathways. Using original clustering approaches, we recently demonstrated that molecular composition of signaling trajectories found by Cadbio} permitted to identify families of functionally-similar trajectories in TGF-beta signaling networks. Beyond TGF-beta signaling, the Cadbiom model is the only dynamic model containing all the cell signaling pathways described in humans, allowing us to explore the regulatory trajectories of more than 600 genes and facilitating the identification of targets therapeutic.

Ph-D thesis defended in 2013

Four theses were defended within the Dyliss team in 2013, on several subjects and applications.

Oumarou Abdou Arbi studied the variability of flux distribution within a metabolic network and its application to diary cows. This was a collaboration with the Pegase laboratory of INRA. [thesis[3]]

Geoffroy Andrieux studied discrete temporal dynamics of signalling network and their application to TGFbeta pathway. This was a collaboration with the IRSET laboratory from Univ. Rennes 1 and Inserm.

Andres Aravena investigated the pruning of regulatory networks and its application to mining bacteria. This was a collaboration with the CMM at universidad de Chile [thesis[5]]

Charles Bettembourg introduced semantic methods for comparing metabolic pathways and their application to chicken. This was a collaboration with the Pegase laboratory of INRA.

Sea Urchin

Dyliss team is in close collaboration with Roscoff Marine Biological Station[10]. We work together on differential and probabilistic models to understand the initiation of the cap-dependant translation in the egg cells of sea urchins. In other words, we study an important mechanism that synthesizes proteins from messenger RNA during the very first minutes of eukaryotic life. This work is a step toward the understanding of eukaryotic translation regulation networks. We used a numeric-based modeling approach to decipher the regulation of protein synthesis following fertilization in sea urchin. This approach based on parcimonious modelling evidenced that two processes are required to explain experimental data: a destabilization of eIF4E:4E-BP complex and a great stimulation of the 4E-BP-degradation mechanism, both rapamycin-sensitive. This model was extended in order to have a better understanding of the role of cyclin B in protein synthesis within minutes after fertilization of sea urchin eggs. The model confirms that regulation of cyclin B biosynthesis is an example of a select protein whose translation is controlled by pathways that are distinct from housekeeping proteins, even though both involve the same cap-dependent initiation pathway. Therefore, this model should help provide insight to the signaling utilized for the biosynthesis of cyclin B and other select proteins.